This invention relates to a process for preparing cephalosporin compounds, and particularly, free acid 3-methoxymethylcephalosporins.
3-Methoxymethylcephalosporins are recognized in the literature. However, a facile and convenient method affording substantial product conversion from readily available starting materials has to date not been available. It is to such a method that this invention is directed.
U.S. Pat. Nos. 3,658,799 and 3,665,003 each describe the conversion of a 3-hydroxymethylcephalosporin to its corresponding 3-alkoxymethylcephalosporin.
One of the methods described in U.S. Pat. No. 3,665,003 involves the use of diazomethane. This method has certain deficiencies. First, an ester protecting group is employed, and this necessitates two additional steps in the preparative sequence, one to incorporate the protecting group and the other to effect its removal. Secondly, diazomethane is both highly toxic and explosive. Its use therefore tends to be greatly limited.
Another method described in U.S. Pat. Nos. 3,658,799 and 3,665,003 involves the use of an activated derivative of an acid HX having a pKa of not more than 4.0 in combination with a 3-hydroxymethylcephalosporin. The resulting 3--XCH.sub.2 cephalosporin compound then is reacted with an alcohol or phenol to obtain the desired 3-etherified hydroxymethyl compound. In this regard, the acid which is employed is a haloacetic acid, specifically and preferably dichloroacetic acid. This method also has a distinct drawback. It too requires the use of a cephalosporin having a protected 4-carboxy group. Failure to suitably protect the 4-carboxy group prior to conversion of the 3-hydroxymethylcephalosporin using a haloacetic acid such as is described in these patents results in formation of substantial quantities of the undesired lactone with little or no formation of the desired 3-methoxymethylcephalosporin. Again, therefore, it is essential in the haloacetic acid process described in these two patents to include the step of blocking the carboxyl group of the cephalosporin starting material at the outset and declocking it upon completion of the reaction.
This invention overcomes these prior art deficiencies and thus is directed to a process for preparing in substantial yield a free acid 3-methoxymethylcephalosporin from its corresponding free acid 3-hydroxymethylcephalosporin. The costly and time-consuming steps of blocking the carboxyl group of the cephalosporin reactant and deblocking that of the product are avoided by the discovery which constitutes the basis of this invention.
Thus, this invention is directed to a process for preparing a 3-methoxymethylcephalosporin of the formula ##STR1## in which R is an acylamino or an imido group which comprises contacting a compound of the formula ##STR2## with at least four equivalents of an activating agent selected from the group consisting of trifluoroacetic anhydride, phosphorus trichloride, phosphorus oxychloride, and thionyl chloride at a temperature of from about -30.degree. C. to about +20.degree. to produce an intermediate compound, separating the resulting intermediate from excess activating agent by treating the reaction mixture at reduced pressure and at a temperature not in excess of about 50.degree. C., and reacting said intermediate with an excess of methanol at a temperature of from about 45.degree. to about 75.degree. C. to produce the aforementioned product.